5-Oxo-2,3-dihydro-imidazo(1,2-a)-s-triazines

ABSTRACT

Compounds of the formula   WHEREIN R1 is phenyl or mono-, di- or tri-substituted phenyl, THE SUBSTITUENTS BEING EACH HALOGEN, METHYL, METHOXY OR TRIFLUOROMETHYL, AND R2 is hydrogen, phenyl or halo-phenyl; THE COMPOUNDS ARE USEFUL AS ANTIDEPRESSANTS.

United States Patent [191 Stable et al.

[ June 3, 1975 5-OXO-2,3-DIHYDRO-IMIDAZO(1,2-A)-S- TRIAZINES [75] Inventors: Helmut Stiihle; Herbert Kiippe;

Werner Kummer, all of Ingelheim am Rhein; Wolfgang Hoefke, Budenheim, all of Germany [73] Assignee: Boehringer Ingelheim GmbH,

Ingelheim am Rhein, Germany 22 Filed: Mar. 12,1974

211 App1.N0.:450,289

[30] Foreign Application Priority Data Mar. 23, 1973 Germany 2314488 [52] US. Cl. 260/249.5; 424/249; 260/309.6 [51] Int. Cl C07d 57/34 [58] Field of Search 260/2495 [56] References Cited UNITED STATES PATENTS 3,840,537 10/1974 Garside et a1 260/2495 Primary Examiner.lohn M. Ford Attorney, Agent, or FirmHammond & Littell [57] ABSTRACT Compounds of the formula phenyl,

the substituents being each halogen, methyl, methoxy or trifluoromethyl, and

R is hydrogen, phenyl or halo-phenyl; the compounds are useful as antidepressants.

14 Claims, N0 Drawings 1 -OXO-2,3-DIHYDRO-IMIDAZO(1,2-A)-S- TRIAZINES This invention relates to novel 5-oxo-2,3-dihydroimidazo[2,3-a]s-triazines, as well as to methods of preparing these compounds.

More particularly, the present invention relates to a novel class of 5-oxo-2,3-dihydro-imidazo[ l,2-a]striazines represented by the formula Method A By subjecting a 2-phenylamino-2-imidazoline of the formula wherein R has the same meanings as in formula I, to a condensation reaction with an N-(halo-methylene or benzylidene) -carbamoyl halide of the formula (III) where R,, R and Y have the meanings previously defined, which are formed by the condensation reaction can normally not be isolated; they very readily and spontaneously cyclize into the desired end products of the formula 1.

Method B By reacting a l-carbamoyl-2-amino-2-imidazoline of the formula n C N \NH2 wherein R has the same meanings as in formula I, with an orthoester of the formula wherein R is alkyl of 1 to 3 carbon atoms, and R has the same meanings as in formula I.

This condensation reaction is preferably performed thermally, in the presence or absence of a solvent medium, at temperatures between and C.

The starting compounds of the formula II are described in Belgian patents Nos. 623,305; 687,656; 687,657; and 705,944.

A compound of the formula III may be prepared, for example, by the methods described by R. Neidlein et al in Tetrahedron Letters 28, 2432 (1965) or by S. Yanagida et al in Bull. Chem. Soc. Japan 44, 2182 (1971).

A compound of the formula V may be obtained by reacting a compound of the formula ll with a carbamic acid ester.

The orthoesters of the formula V] are well-known compounds.

The following examples illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.

EXAMPLE 1 8-(2,6-Dichloro-phenyl)-7-(p-chloro-phenyl)-5-oxo- 2,3-dihydro-imidazo[ l,2-a]s-triazine by method A 2.3 gm (0.01 mol) of 2-[(2',6'-dichloro-phenyl)- amino]-2-imidazoline were dissolved in 50 ml of absolute benzene, 5 ml of triethylamine were added to the solution, the resulting mixture was heated to the boiling point, and, while maintaining it at the boiling point, a solution of 2.4 gm 0.01 mol) of N-(a-chloro-4- chlorobenzylidene )-carbamoyl chloride in 25 ml of absolute benzene was added dropwise over a period of about 15 minutes. The reaction mixture was then boiled for 15 minutes more and was subsequently evaporated to dryness in vacuo. The residue was stirred with dilute hydrochloric acid (to remove impurities which go into solution) and then vacuum-filtered. The filter cake was washed first with water, then with ethanol and finally with ether, blotted on clay, and recrystallized from chloroform, yielding 2.25 gm (52.0 percent of theory) of the compound of the formula Q'I I c.

which had a melting point of 320322C. The compound was insoluble in water, dilute hydrochloric acid, ethanol and ether, and soluble in dimethylsulfoxide.

EXAMPLE 2 8-(2,6-Dichloro-phenyl)-2,3-dihydro-5-oxoimidazo[ l ,2-a]s-triazine by method B A mixture consisting of 2.73 gm (0.01 mol) of lcarbamoyl-2-[(2',6'-dichloro-phenyl)-amino]-2- imidazoline (m.p. 257259C), ml of ethyl orthoformate and ml of hexamethylphosphoric acid -triamide (HMPT) was refluxed for two hours. Thereafter, the reaction mixture which contained three different new compounds, as determined by thin-layer chromatography was diluted with 200 ml of benzene, and the resulting HMPT/benzene solution was repeatedly washed with water. The organic phase was evaporated in vacuo, the residue was dissolved in dilute hydrochloric acid, and the resulting solution was fractionally extracted at gradually increasing pH-values. Those fractions containing the desired compound, as determined by thin-layer chromatography, were combined and evaporated, yielding 0.15 gm of the compound of the formula i?" c1 fin which had a melting point of l55l57C.

EXAMPLE 3 Using a procedure analogous to that described in Example 38.6 percent of theory of 7-(p-chlorophenyl)-8-(2'-chloro-6-methyl-phenyl)-5-oxo-2,3- dichloro-imidazo[ l,2-a]s-triazine, m.p. 327329C, of the formula H30 Cil.

was obtained from 2-[(2-chloro-6-methyl-phenyl)- amino]-2-imidazoline and N-(a-chloro-4-chloro-benzylidene)-carbamoyl chloride.

EXAMPLE 4 Using a procedure analogous to that described in Example I, 26.9 percent of theory of 7-(p-chlorophenyl)-8-(2',6'-dichloro-4-bromo-phenyl)-5-oxo- 2,3-dihydro-imidazo[ l,2-a]s-triazine, mp. 285-288C, of the formula was obtained from 2-[(2',6-dichloro-4'-bromophenyl)-amino]-2-imidazoline and N-(a-chloro-4- chloro-benzylidene)-carbamoyl chloride.

EXAMPLE 5 EXAMPLE 6 Usinga procedure analogous to that described in Example l, 39.0 percent of theory of 7-phenyl-8-(2', dichloro-phenyl )-5-oxo-2,3-dihydro-imidazo[ 1,2-a striazine, m.p. 23'9.5-242.5C, was obtained from 2- [(2',6-dichloro-phenyl)-amino]-2-imidazoline and N- (oz-chloro-benzylidene)-carbamoyl chloride.

EXAMPLE 7 Using a procedure analogous to that described in Example l, 43.2 percent of theory of 7-(m-chlorophenyl)-8-(2,6'-dichloro-phenyl)-5-oxo-2,3-dihydroimidazo[l,2-a]s-triazine, m.p. 248-25lC, was obtained from 2-[(2',6'-dichloro-phenyl)-amino]-2- imidazoline and N-(a-chloro-3-chloro-benzylidene)- carbamoyl chloride.

EXAMPLE 8 Using a procedure analogous to that described in Example I, 32.2 percent of theory of 7-(m-chlorophenyl)-8-(2-chloro-6-methyl-phenyl)-5-oxo-2,3- dihydro-imidazo[l,2-a]s-triazine, m.p. 229230C, was obtained from 2-[(2-chloro-6-methyl-phenyl)- amino]-2-imidazoline and N-(a-chloro-3-chloro-benzylidene)-carbamoyl chloride.

EXAMPLE 9 Using a procedure analogous to that described in Example I, 51.0 percent of theory of 7-(m-chlorophenyl)-8-(2-trifiuoromethyl-phenyl)-5-oxo-2,3- dihydro-imidazo[l,2-a]s-triazine, m.p. 220222C, of the formula was obtained from 2-[(2-trifluoromethyl-phenyl)- amino]-2-imidazoline and N-(oz-chloro-3-chloro-benzylidenej-carbamoyl chloride.

EXAMPLE 10 Using a procedure analogous to that described in Example 1, 38.2 percent off theory of 7-(m-chloro- I phenyl)-8-(2'-chloro 4-methyl-phenyl)-5-oxo-2,3- dihydro-imidazo[l,2-a]s-triazine, m.p. 245247C, was obtained from 2-[(2-chloro-4'-methyl-phenyl)- amino]-2-imidazoline and N-(a-chloro-3-chloro-benzylidene)-carbamoyl chloride.

EXAMPLE 1 1 Using a procedure analogous to that described in Example l, 6.2 percent of theory of 7-(m-chloro-phenyl)- 8-phenyl-5-oxo-2,3-dihydro-imidazo[ 1,2-a]s-triazine, m.p. 2l3-216C, was obtained from 2-(phenylamino)-2-imidazoline and N-(a-chloro-3-chloro-benzylidene)-carbamoyl chloride.

EXAMPLE 12 6 substitution, is accompanied by less pronounced antiulcerogenic,, antiphlogistic, diuretic, hypotensive and- /or analgesic activities.

For pharmaceutical purposes the compounds according to the present invention are administered to warmblooded animals perorally, parenterally or rectally as active ingredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like. One effective antidepressant dosage unit of the compounds according to the present invention is from 0.0016 to 0.167 mgm/kg body weight.

The following examples illustrate a few pharmaceutical dosage unit compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of putting the invention into practical use. The .parts are parts by weight unless otherwise specified.

EXAMPLE l3 Coated pills The pill core composition is compounded from the following ingredients:

2-a]s-triazine 5.0 parts Lactose 23.5 do. Corn starch 20.0 do. Gelatin 1.0 do. Magnesium stearate 0.5 do

Total 50.0 parts Preparation The imidazo-s-triazine compound, the lactose and the corn starch are intimately admixed with each other, the mixture is uniformly moistened with an aqueous 10% solution of the gelatin, and the moist mass is granulated by forcing it through a l mm-mesh screen. The granulate is then dried at 40C, again passed through the screen, admixed with the magnesium stearate, and the resulting composition is compressed into 50 mgmpill cores, which are subsequently coated in conventional fashion with a thin shell consisting essentially of a mixture of sugar, titanium dioxide, talcum and gum arabic, and finally polished with beeswax. Each coated pill contains 5 mgm of the imidazo-s-triazine compound and is an oral dosage unit composition with effective antidepressant action.

EXAMPLE 14 Tablets The tablet composition is compounded from the following ingredients:

dihydro-imidazo[ l,2-a]s-triazine 2.0 parts Lactose 300 do. Corn starch 40.0 do. Colloidal silicic acid 2.0 do. Magnesium stearate l d Total .0 parts EXAMPLE l Suppositories The suppository composition is compounded from the following ingredients:

2-a]s-triazine 5.0 parts Lactose 195.0 do. Suppository base (e.g. cocoa butter) 1500.0 do.

Total l70().0 parts Preparation A mixture of the imidazo-s-triazine and the lactose is uniformly blended, with the aid of an immersion homogenizer, into the suppository base which had previously been melted and cooled to 40C. 1700 mgmportions of the resulting mixture are poured into cooled suppository molds and allowed to harden therein. Each suppository contains 5 mgm of the imidazo-s-triazine compound and is a rectal dosage unit composition with effective antidepressant action.

Analogous results are obtained when any one of the other imidazo-s-triazines embraced by formula I is substituted for the particular imidazo-s-trizine in Example 13 through 15. Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes'and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. A compound of the formula wherein R is phenyl or mono-, dior tri-substituted phenyl,

the substituents being each selected from the group consisting of halogen, methyl, methoxy and trifluoromethyl, and

R is hydrogen, phenyl or halo-phenyl.

2. A compound of claim 1, wherein R is phenyl, methyl-chloro-phenyl, dichloro-phenyl,

dichloro-bromo-phenyl or trifluoromethyl-phenyl, and

R is hydrogen, phenyl or chloro-phenyl.

3. The compound of claim 2 which is 8-(2,6- dichloro-phenyl)-7-(p-chloro-phenyl)-5-oxo-2,3- dihydro-imidazo[ l,2-a]s-triazine.

4. The compound of claim 2 which is 8-(2, 6'- dichloro-phenyl)-2,3-dihydro-5-oxo-imidazo[ l,2-a]striazine.

5. The compound of claim 2 which is 7-(p-chlorophenyl)-8-(2-chloro-6-methyl-phenyl)-5-oxo-2,3- dichloro-imidazo[ l,2-a]s-triazine.

6. The compound of claim 2 which is 7-(p-chlorophenyl)-8--(2,6-dichloro-4-bromo-phenyl)-5-oxo- 2,3-dihydro-imidazol l ,2-a]s-triazine.

7. The compound of claim 2 which is 7-(p-chlorophenyl)8-(2'-chloro-4-methyl-phenyl)-5-oxo-2,3- dihydro-imidazo[ 1,2-a ]s-triazine.

8. The compound of claim 2, which is 7-phenyl-8- (2',6-dichloro-phenyl)-5-oxo-2,3-dihydroimidazo[ l,2-a]s-triazine.

9. The compound of claim 2 which is 7-(m-chlorophenyl)-8-(2,6-dichloro-phenyl)-S-oxo-2,3-dihydroimidazo[ 1,2-a]s-triazine.

10. The compound of claim 2 which is 7-(m-chlorophenyl)-8-(2'-chloro-6-methyl-phenyl)-5-oxo-2,3- dihydro-imidazo[ l,2-a]s-triazine.

11. The compound of claim 2 which is 7-(m-chlorophenyl)-8-(2-trifluoromethy1-phenyl)-5-oxo-2,3- dihydro-imidazo[ l ,2-a]s-triazine.

12. The compound of claim 2 which is 7-(m-chlorophenyl)-8-(2'-chloro-4-methyl-phenyl)-5-oxo-2,3- dihydro-imidazo[ l,2-a]s-triazine.

13. The compound of claim 2 which is 7-(m-chlorophenyl)-8-phenyl-5-oxo-2,3-dihydro-imidazo[ l ,2-a]striazine. i

14. The compound of claim 2 which is 7-(m-chlor0- phenyl)-8-(2-chloro-3'-rnethyl-phenyl)-5-oxo-2,3- dihydro-imidazo[ 1 ,2-a ]s-triazine. 

1. A COMPOUND OF THE FORMULA
 1. A compound of the formula
 2. A compound of claim 1, wherein R1 is phenyl, methyl-chloro-phenyl, dichloro-phenyl, dichloro-bromo-phenyl or trifluoromethyl-phenyl, and R2 is hydrogen, phenyl or chloro-phenyl.
 3. The compound of claim 2 which is 8-(2'',6''-dichloro-phenyl)-7-(p-chloro-phenyl)-5-oxo-2,3-dihydro-imidazo(1,2 -a)s-triazine.
 4. The compound of claim 2 which is 8-(2'', 6''-dichloro-phenyl)-2,3-dihydro-5-oxo-imidazo(1,2-a)s-triazine.
 5. The compound of claim 2 which is 7-(p-chloro-phenyl)-8-(2''-chloro-6''-methyl-phenyl)-5-oxo-2,3-dichloro -imidazo(1,2-a)s-triazine.
 6. The compound of claim 2 which is 7-(p-chloro-phenyl)-8-(2'', 6''-dichloro-4''-bromo-phenyl)-5-oxo-2,3-dihydro-imidazo(1,2-a)s-triazine.
 7. The compound of claim 2 which is 7-(p-chloro-phenyl)-8-(2''-chloro-4''-methyl-phenyl)-5-oxo-2,3-dihydro -imidazo(1,2-a)s-triazine.
 8. The compound of claim 2, which is 7-phenyl-8-(2'',6''-dichloro-phenyl)-5-oxo-2,3-dihydro-imidazo(1,2-a)s -triazine.
 9. The compound of claim 2 which is 7-(m-chloro-phenyl)-8-(2'', 6''-dichloro-phenyl)-5-oxo-2,3-dihydro-imidazo(1,2-a)s-triazine.
 10. The compound of claim 2 which is 7-(m-chloro-phenyl)-8-(2''-chloro-6''-methyl-phenyl)-5-oxo-2,3-dihydro -imidazo(1,2-a)s-triazine.
 11. The compound of claim 2 which is 7-(m-chloro-phenyl)-8-(2''-trifluoromethyl-phenyl)-5-oxo-2,3-dihydro -imidazo(1,2-a)s-triazine.
 12. The compound of claim 2 which is 7-(m-chloro-phenyl)-8-(2''-chloro-4''-methyl-phenyl)-5-oxo-2,3-dihydro -imidazo(1,2-a)s-triazine.
 13. The compound of claim 2 which is 7-(m-chloro-phenyl)-8-phenyl-5-oxo-2,3-dihydro-imidazo(1,2-a)s-triazine. 